Lung cancer is the leading cancer killer in the US and accounts for more deaths than the next three most common cancers combined (colon, breast, prostate). The annual cost of lung cancer treatment is over $10 billion. Unfortunately, the current five year survival rate for non-small-cell lung cancer (NSCLC) patients is less than 15% due to the prevalence of people diagnosed in advanced stages of the disease and the propensity of lung cancer to develop resistance to current therapies. A clear need exists for new treatment strategies. Previously, it has been shown that dopamine (DA) and D2 receptor (D2R) agonists inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis and tumor growth in mice. Preliminary preclinical data demonstrate that lung tumor bearing mice treated with FDA-approved D2R agonist, cabergoline (Dostinex(R)), exhibit reduced lung tumor growth. A signaling molecule downstream of D2R, called dopamine and cyclic-AMP- regulated phosphoprotein (DARPP-32) and its amino-truncated transcript variant t-DARPP, have been shown to be upregulated in many adenocarcinomas and contribute to drug resistance. The goal of this project is to identify how the DA signaling pathway can be manipulated in both lung endothelium and cancer cells as a NSCLC therapy. The central hypothesis is the abrogation of DARPP-32 or t-DARPP expression in tumor cells and activation of D2R signaling in endothelial cells can inhibit cancer cell drug resistance and angiogenesis, respectively, and improve the clinical outcome of lung cancer patients. First, it will be determined whether activation of endothelial DA signaling prevents lung tumor growth and improves the efficacy of cytotoxic NSCLC therapies. In Aims 2 and 3, experiments will elucidate the role of DA signaling effectors, DARPP-32 and t-DARPP, in lung tumor cell growth and drug resistance. This work is significant because it aims to improve the poor survival rate of NSCLC patients through the development of new targeted therapies and approaches to identify and overcome tumor drug resistance. This project is innovative because therapeutic manipulation of DA signaling pathway remains unexplored and treatment strategies for combatting drug resistance in lung cancer have not been identified. The results will have a collective impact because new NSCLC therapies and drug resistance treatments will improve the quality life and outlook of many Americans suffering from this dismal disease. The candidate intends to start an independent laboratory focusing on the development of new cancer therapies by studying the mechanisms of drug resistance and tumor angiogenesis through the use of genetic animal models. To date, the applicant's research demonstrates an aptitude for molecular biology and biochemistry. The goal for the mentored phase of training is to gain experience with the use of genetic animal models. The investigator will interact with his primary mentor and a mentoring committee that has extensive experience with the creation, use and manipulation of genetic animal models. The candidate is well qualified to conduct studies proposed in the R00 phase independently while transitioning to an independent career. The completion of this project and the training received at the Mayo Clinic, a leading institution in the field of cancer research, will prepare the candidate to be an outstanding researcher in the field of cancer biology.